Insulin secreting cells derived from human embryonic stem cells (hES cells; NIH Code UC06 {HSF6 line from UCSF}; NIH Code WA01 (H1 line from WiCell) and NIH code WA07 (H7 line from WiCell), offer one of the most promising strategies for curing-not just treating-diabetes. Driving beta-cell differentiation from hES cells is an important experimental challenge. Here we build on inducing this differentiation by utilizing the power of chimeric proteins imported through selective receptors. Aim 1. Construction of novel chimeric proteins that promote the differentiation of stem cells into insulin secreting cells. We are now able to fuse two genes at the DNA level to produce a single fusion protein, known as chimeric protein, composed of a cell targeting component and an active component, which enables them to recognize, internalize, and alter cells expressing specific receptors. We will fuse a targeting moiety to the PDX-1 transcription factor that is involved in normal beta-islet development, to cause stem cells to differentiate into beta-cells. Aim 2. To follow the differentiation of the chimeric protein treated stem cells into beta-cells. Does the binding and internalization of the chimeric protein into the hES cells cause them to differentiate into beta-cells? Is only one treatment needed to promote differentiation, or is there a need for repetitive treatments? What is the time period in which we should treat the cells? Aim3. Can chimeric protein treated cells maintain their beta-cell characteristics and ability to maintain a normal glucose level in a mouse NOD-SCID diabetes model?